The present invention relates to substituted [1,2,4]-triazole bicyclic adenosine A2a receptor antagonists, the use of said compounds in the treatment of central nervous system diseases, in particular Parkinson's disease, and to pharmaceutical compositions comprising said compounds.
Adenosine is known to be an endogenous modulator of a number of physiological functions. At the cardiovascular system level, adenosine is a strong vasodilator and a cardiac depressor. On the central nervous system, adenosine induces sedative, anxiolytic and antiepileptic effects. On the respiratory system, adenosine induces bronchoconstriction. At the kidney level, it exerts a biphasic action, inducing vasoconstriction at low concentrations and vasodilation at high doses. Adenosine acts as a lipolysis inhibitor on fat cells and as an antiaggregant on platelets.
Adenosine action is mediated by the interaction with different membrane specific receptors which belong to the family of receptors coupled with G proteins. Biochemical and pharmacological studies, together with advances in molecular biology, have allowed the identification of at least four subtypes of adenosine receptors: A1, A2a, A2b and A3. A1 and A3 are high-affinity, inhibiting the activity of the enzyme adenylate cyclase, and A2a and A2b are low-affinity, stimulating the activity of the same enzyme. Analogs of adenosine able to interact as antagonists with the A1, A2a, A2b and A3 receptors have also been identified.
Selective antagonists for the A2a receptor are of pharmacological interest because of their reduced level of side affects. In the central nervous system, A2a antagonists can have antidepressant properties and stimulate cognitive functions. Moreover, data has shown that A2a receptors are present in high density in the basal ganglia, known to be important in the control of movement. Hence, A2a antagonists can improve motor impairment due to neurodegenerative diseases such as Parkinson's disease, senile dementia as in Alzheimer's disease, and psychoses of organic origin.
Some xanthine-related compounds have been found to be A1 receptor selective antagonists, and xanthine and non-xanthine compounds have been found to have high A2a affinity with varying degrees of A2a vs. A1 selectivity. Certain imidazolo- and pyrazolo-substituted triazolo-pyrimidine adenosine A2a receptor antagonists have been disclosed previously, for example in WO 95/01356; WO 97/05138; and WO 98/52568. Certain pyrazolo-substituted triazolo-pyrimidine adenosine A2a receptor antagonists are disclosed in U.S. Ser. No. 09/207,143, filed May 24, 2001. Certain imidazolo-substituted triazolo-pyrimidine adenosine A2a receptor antagonists are disclosed in U.S. Provisional Application 60/329,567, filed Oct. 15, 2001. U.S. Pat. No. 5,565,460 discloses certain triazolo-triazines as antidepressants; EP 0976753 and WO 99/43678 disclose certain triazolo-pyrimidines as adenosine A2a receptor antagonists; and WO 01/17999 discloses certain triazolo pyridines as adenosine A2a receptor antagonists.